tbuckley/cabot-search huggingface dataset:
QOL-12. “I’M JUST LIKE A BASKET FULL OF PROBLEMS”: QUALITATIVE STUDY OF COGNITIVE DYSFUNCTION AND QUALITY OF LIFE IN GLIOMA SURVIVORS
Authors: Kathleen Van Dyk, Lucy Wall, Benjamin Ellingson, Nicholas An, Albert Lai, Timothy Cloughesy, Eden R Brauer, Phioanh L Nghiemphu
Journal: Neuro-Oncology (2022)

Abstract For glioma survivors, cognitive impairment can be a central determinant of quality of life, but we need better understanding of their unique challenges and supportive care needs. In this qualitative study, we aimed to explore the post-treatment experiences of cognitive and functional challenges and their impact on quality of life from the perspectives of glioma survivors. Glioma survivors in an observational study were invited to participate in an in-depth qualitative interview. Using a semi-structured interview guide, interviews were audio-recorded and transcribed verbatim. Data were analyzed using a reflexive thematic analysis approach to develop key themes to inform clinical practice. Participants (n=9) ranged in age from 29 to 72 years, and were at least 4 years post-diagnosis. Under the overarching survivorship theme, three key themes were developed. The first theme, “Learning what my brain can and can’t handle,” centered on functional challenges related to cognitive impairments, including difficulties at work and managing home and family responsibilities. In response, participants described generating their own strategies to manage cognitive limitations in daily activities. The second theme, “Such an important crossroads”, reflected the significant emotional impact of persisting impairments (e.g., frustration, disappointment, reduced self-esteem, acceptance), increased anxiety around an uncertain future, and a shift in personal values towards an increased sense of gratitude, crystalizing of intentions, and focus on things of greatest importance. The final theme, “A solid foundation of people around me”, referred to the necessity of social support, in both emotional and instrumental terms. Many expressed a desire for and appreciation of coping tools and support for the support people in their lives. Nearly all participants expressed interest in cognitive rehabilitation – whether or not they were experiencing significant cognitive problems. These findings have implications for clinical practice and can inform the development of effective patient-centered supportive care interventions in this population.
SURG-31. UTILITY OF TRANEXAMIC ACID (TXA) FOR RESECTION OF INTRACRANIAL MENINGIOMAS: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Nolan Brown, Brandon Nguyen, Andrew Nguyen, Ryan Beyer, Mark Harris, Rohin Singh, Shane Shahrestani, Ahmed Mohyeldin
Journal: Neuro-Oncology (2022)

Abstract Due to its anti-fibrinolytic action, tranexamic acid (TXA) can be utilized to help maintain hemostasis during surgical operations. With respect to surgery for intracranial tumors, we hypothesize that TXA could help mitigate blood loss during resection of highly vascular tumors such as meningiomas. We therefore conducted a systematic review of the literature and meta-analysis to analyze the effects of TXA administration in patients undergoing surgical resection of intracranial meningioma. Study inclusion criteria were (1) primary data articles describing use of TXA in surgical resection of meningioma. In this meta-analysis, which included four primary comparative studies, outcome measurements between TXA and non-TXA groups were compared. Primary outcomes included operative length, complications, transfusion requirements, estimated blood loss, and postoperative Hb for TXA versus non-TXA (control) groups. Pooled-comparative analysis was conducted for each of these perioperative variables and formal meta-analysis was applied toward statistically significant parameters. A total of 221 patients were analyzed (110 TXA, 111 non-TXA). Patient age (p = 0.1632), gender (p = 0.8317), and tumor location (p = -.8334) were similar for TXA and control groups. TXA was associated with decreased complication rate (logRR: -0.85; CI95% = -1.49 to -0.22; p = 0.0087), decreased transfusion requirement (logRR: -0.50; CI95% = -0.92 to -0.08; p = 0.0039), reduced blood loss (SMD: -1.76; CI95% = -3.21 to -0.31; p &amp;lt; 0.0001), and increased postoperative Hb (SMD: 0.46; CI95% = -0.15 to 1.07; p &amp;lt; 0.0001). In three trials, TXA was administered intravenously as a loading dose of 20 mg/kg for 20 minutes preoperatively with an intraoperative maintenance rate of 1mg/kg/hr; in one trial, administration design was identical except that infusion rate of the 20 mg/kg preoperative loading dose was unspecified. TXA may be associated with reduced complications, transfusion requirements, perioperative estimated blood loss, and increasedpostoperative Hb when administered perioperatively for surgical resection of intracranial meningiomas.
PATH-04. CURRENT STATUS AND PROSPECTS OF MALIGNANT BRAIN TUMOR TREATMENT IN CANCER GENOMIC MEDICINE
Authors: Shinichiro Koizumi, Tomohiro Yamasaki, Tomoya Oishi, Kazuhiko Kurozumi
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION The cancer gene panel test was covered by insurance in June 2019 in Japan. Our institution started the test in May 2020 and has experienced 16 cases. We will report on the current status and future prospects. METHODS The subjects were 16 patients (Average age 48.4) who underwent the cancer gene panel test with FoundationOne CDx. [Results] The cases included 9 glioblastomas, 3 anaplastic astrocytomas, 2 anaplastic oligodendrogliomas, an ependymoma, and a pituitary carcinoma. On average, 11.0 genetic changes were detected totally, oncogene mutations were 4.4, and gene mutations of unknown relevance to cancer were 5.6. Major oncogene mutations were IDH1 mutation in 5 cases, ATRX mutation in 2 cases, TP53 mutation in 9 cases, CDKN2A/2B mutation in 5 cases, and BRAF V600E mutation in 1 case. Based on our results, a 25-year-old man with BRAF V600E mutation and a 47-year-old male with IDH1 mutation could be given molecular-targeted drugs. Furthermore, a 59-year-old male with pituitary carcinoma had more than 10 mut/Mb in tumor mutational burden (TMB), indicating that anti-PD-1 antibody drugs can be administered. The chance of finding an appropriate drug by cancer gene panel test is approximately 10-20%. In cases that are resistant to standard treatment, the benefits can be expected if the drugs associated with the cancer gene panel test can be used. CONCLUSIONS Comprehensive cancer gene panel test has the potential to provide personalized medicine. And we suggest that the active use of cancer gene panel test may contribute to the development of new drugs with high response rates and the improvement of prognosis.
EPCO-07. NON-GENOMIC DETERMINANTS OF TUMOR CELL PHENOTYPES IN ADULT GLIOBLASTOMA
Authors: Zsolt Zador, Nicholas Mikolajewicz, Hong Han, Chirayu Chokshi, Chitra Venugopal, Will Maich, Moffat Jason, Sheila Singh
Journal: Neuro-Oncology (2022)

Abstract Non-genomic determinates of oncogenic cellular phenotypes is an emerging concept that expanded our model of tumor hallmarks. We hypothesized that oncogenic programs in adult glioblastoma (GBM) such as angiogenesis, proliferation, DNA repair, epithelial to mesenchymal transition and quiescent states are achieved independently of mutational background or clonal linage. We therefore explored the assortations of large-scale chromosomal rearrangements and canonical driver mutations with oncogenic programs in single cell RNA sequencing (scRNA-seq) of over 3000 tumor cells in 4 adult GBM using open data. We find recurring patterns where tumor cells from diverse mutational background and clonal linage converge upon oncogenic tumor phenotypes. We validate this observation in 9 tumors comprising over 16,000 cells and in xenograft animal models of GBM pre- and post temozolamide treatment. We finally explore the epigenetic associations of oncogenic phenotypes via computational label transfer from scRNA-seq to chromatic accessibility data from single cell ATAC sequencing (scATAC-seq). We find open genomic regions associated with canonical regulators, such as the highly oncogenic mesenchymal phenotype driven by TWIST1. Our results suggest a paradigm shift towards non-genetic determinants of oncogenic phenotypes in GBM complementing the conventional concept of cancer clonal evolution.
ANGI-03. TARGETING ANGIOGENIC PATHWAYS IN COMBINATION WITH OHSV THERAPY IN GBM
Authors: Karina Vazquez-Arreguin, Yoshihiro Otani, Kimberly Rivera-Caraballo, Pei Guangsheng, Zhao Zhongming, Balveen Kaur
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is the most aggressive brain malignancy, which despite continuing worldwide efforts to develop new therapies, remains a deadly disease with limited treatment options. The asparagine hydroxylase factor inhibiting HIF (FIH1) is located in chromosome 10q24, a region often deleted in GBM, suggesting a tumor protective role. FIH1 has been implicated in GBM as an inhibitor of HIF1α-mediated transcription of VEGF-A, leading to decreased angiogenesis. We previously showed that oncolytic HSV (oHSV) infection reduces the expression FIH1 via a virus encoded miRNA. Furthermore, we have found that FIH1 also negatively regulates NOTCH signaling, which is elevated following oHSV treatment. Thus, we hypothesize that FIH1 reconstitution in tumors will block pro-tumorigenic NOTCH and HIF1α signaling. Using FIH1-overexpressing GBM cells we observed a reduction in vascular permeability, measured by intravital imaging, and decreased expression of angiogenesis markers. In vivo, combination of FIH1 overexpression with oHSV treatment resulted in enhanced survival in mice bearing intracranial GBM tumors. Furthermore, FIH1 overexpression correlated with the enrichment of genes associated with oxidative phosphorylation and ROS pathways, suggesting the potential for multi-modality therapeutic strategies.
TMET-36. ACID CERAMIDASE INHIBITION EXPLOITS SPHINGOLIPID VULNERABILITIES IN IDH MUTANT GLIOMAS
Authors: Faris Zaibaq, Tyrone Dowdy, Mioara Larion
Journal: Neuro-Oncology (2022)

Abstract The presence of the IDH mutation in gliomas is a major classifier of brain tumor subtypes and has several important implications for cancer growth. Our recent work uncovered that IDH-mutant tumors are susceptible to increased apoptosis via alterations of the sphingolipid pathway due to their excess production of pro-apoptotic ceramides over pro-proliferative sphingosine 1-phosphate (S1P). To that end, we proposed that this rheostat can be modulated to induce cell death in IDHmut tumors by targeting acid ceramidase, a critical sphingolipid enzyme in gliomas. We hypothesize that pharmacological inhibition of acid ceramidase will increase ceramide levels and therefore induce apoptosis in IDHmutgliomas. Using a preliminary drug screen, we have identified a group of haloacetate C2-ceramide derivatives known as SOBRACs that potently inhibit acid ceramidase. We selected five candidate compounds from this family and assessed the effectiveness of each drug in 3 I IDHmut (BT142, TS603, &amp; U251mut) and 3 IDHmut (GSC923, GSC827, U251wt) patient-derived glioma cell lines, as well as non-immortalized normal human astrocytes, using the CCK8 cell viability assay. Our results indicate that the SOBRAC drugs are nearly 10 times more potent in IDH-mutant tumors compared to IDHmut cell lines. Additionally, the SOBRAC drugs are more effective than other known acid ceramidase inhibitors, making them attractive as potential novel therapeutics. To date, azide-SOBRAC is the most potent drug in the family, with EC50 value of 300 nM in BT142 cells (IDHmutmut
PATH-40. A GIANT CELL LESION RESEMBLING REPARATIVE GIANT CELL GRANULOMA WITH FN1-TEK FUSION, IN THE SPECTRUM OF CALCIFIED CHONDROID MESENCHYMAL NEOPLASM?
Authors: Xiao-Tang Kong, Mehrnaz Movassaghi, Mari Perez-Rosendahl, Yoon Choi, William Yong
Journal: Neuro-Oncology (2022)

Abstract A newly described entity called “calcified chondroid mesenchymal neoplasms” includes chondroid neoplasms with variable amounts of calcification and FN1 fusions [Liu et al, Mod Pathol 2021]. We report a case of a left temporal bone giant cell granuloma-like lesion that also shows an FN1-TEK fusion. Close monitoring with MRI images after surgery has showed no recurrence. Case report: a 33-year-old male developed left jaw pain and he was diagnosed with a temporomandibular joint disorder. He felt left ear fullness and 2 years later experienced severe pain and swelling in the left temporal region. Imaging showed an expansile osseous lesion with multi-cystic components involving the left sphenoid bone as well as all portions of the temporal bone including the mastoid, middle ear cavity, and glenoid fossa. Pathology showed a hemorrhagic giant cell lesion that was negative for H3G34W mutation and USP6 rearrangement, suggesting a reparative giant cell granuloma. A subsequent NGS with the Tempus 648 gene panel did not identify somatic or germline mutations, but an additional Tempus RNA fusion test found a FN1-TEK fusion suggesting the possibility of neoplasia. Close monitoring with brain MRI over past 9 months has shown no signs of recurrence. DISCUSSION A recent small series describes a novel entity called calcified chondroid mesenchymal neoplasm that has FN-1 fusions including a FN1-TEK fusion in one case. The case in that series with FIN1-TEK fusion also showed prominent giant cells. It is unclear whether giant cell granuloma-like lesions with FN1-TEK fusion belong in the calcified chondroid mesenchymal neoplasm spectrum or are a separate non-neoplasm entity that shares the same alteration. More studies are warranted.
CTNI-39. FIGHT-209: A PHASE 2, OPEN-LABEL, MULTICENTER STUDY OF PEMIGATINIB IN PATIENTS WITH PREVIOUSLY TREATED GLIOBLASTOMA OR OTHER PRIMARY CENTRAL NERVOUS SYSTEM TUMORS WITH ACTIVATING FGFR1-3 ALTERATIONS
Authors: Manmeet Ahluwalia, Enrico Franceschi, Luisa Veronese, Natalia Oliveira, Xin Li, Martin van den Bent
Journal: Neuro-Oncology (2022)

Abstract Fibroblast growth factor receptor (FGFR) signaling plays a role in progression of gliomas. Pemigatinib is a potent selective inhibitor of FGFR1-3, with demonstrated antitumor activity in patients with cholangiocarcinoma harboring FGFR2 fusions/rearrangements. The FIGHT-209 study will evaluate pemigatinib treatment for patients with glioblastoma or other primary central nervous system tumors harboring activating FGFR mutations or fusions/rearrangements. Eligible patients are adults with a radiologically measurable and histologically or molecularly confirmed recurrent glioblastoma, other diffuse glioma, or circumscribed astrocytic tumors harboring a FGFR1-3 gene alteration or fusion/rearrangement. Patients must have Karnofsky performance status ≥ 60, life expectancy ≥ 12 weeks, and documented disease progression after prior therapy with no available therapy likely to provide clinical benefit. Exclusion criteria include prior treatment with FGFR or VEGF/VEGFR inhibitors (other than bevacizumab for radiation necrosis), evidence of corneal or retinal disorder, or history of calcium or phosphate homeostasis disorder. Patients will be assigned to 1 of 3 cohorts based on genomic testing: A: glioblastoma with FGFR1-3 fusions/rearrangements; B: other CNS tumors with FGFR1-3 fusions/rearrangements; C: glioblastoma or other CNS tumors with FGFR1-3 activating mutations. Patients will receive pemigatinib 13.5 mg administered orally QD on a 21-day treatment cycle (2 weeks on/1 week off). Hyperphosphatemia, an on-target pharmacologic effect of FGFR inhibition, will be managed with diet modification, phosphate binders, diuretics, or dose reduction. Treatment will continue until disease progression or unacceptable toxicity. Primary endpoints are objective response rate (ORR) in cohorts A and B based on response assessment in neuro-oncology and assessed by ICR. Secondary endpoints include ORRs in cohorts A and B combined, in all cohorts, and in cohort C alone and the following endpoints for cohorts A and B individually: disease control rate, progression-free survival, duration of response, and overall survival. Safety and tolerability will also be assessed. Clinical trial information: NCT05267106
CTNI-45. CLINICORADIOLOGICAL AND HISTOPATHOLOGICAL CHARACTERISTICS AND TREATMENT OUTCOMES OF CEREBRAL ASTROBLASTOMA IN CHILDREN: A SINGLE-INSTITUTION EXPERIENCE
Authors: Jung Won Choi, Chiman Jeon
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE Astroblastoma (AB) is a rare glial tumor. The optimal treatment and prognosis of this tumor remain unclear. The authors retrospectively analyzed the clinical characteristics, neuroimaging findings, histopathological results, and treatment outcomes of 7 patients with AB. METHODS The study comprised 7 patients with pathologically proven AB who were surgically treated at Samsung Medical Center from November 1994 to January 2019. Clinicoradiological, histopathological, and surgical records were reviewed. RESULTS The patients included 5 girls (71.4%) and 2 boys (28.6%), with a median age of 13 years. All patients showed contrast enhancement on preoperative MRI: 5 ABs (71.4%) showed a concomitant solid and cystic appearance, and 2 (28.6%) demonstrated a solid appearance. ABs in 6 patients (85.7%) showed a well-circumscribed, characteristic "bubbly" appearance on T2-weighted MRI. Gross-total resection (GTR) was achieved in all cases (100%). Six patients (85.7%) were diagnosed with high-grade AB and 1 (14.3%) with low-grade AB. Six (85.7%) of the 7 patients received adjuvant treatment after resection, including 5 (83.3%) with AB who received chemotherapy and radiotherapy and 1 (16.7%) who received proton therapy alone. The median clinical follow-up duration was 96 months (range 48-189 months). Two patients experienced recurrence, and all patients in this series were alive at the last follow-up. CONCLUSIONS In this study, the clinicoradiological and histopathological features of AB were described. Based on the authors' limited experience with 7 cases, resection with the goal of GTR is currently the mainstream treatment for AB, and adjuvant radiation treatment should be considered after surgery.
EXTH-47. PRECLINICAL EFFICACY OF LP-184, A TUMOR SITE ACTIVATED SYNTHETICALLY LETHAL THERAPEUTIC, IN GLIOBLASTOMA
Authors: Bachchu Lal, Aditya Kulkarni, Joseph McDermott, Hernando Lopez-Bertoni, Kishor Bhatia, Panna Sharma, John Laterra
Journal: Neuro-Oncology (2022)

Abstract Temozolomide (TMZ) is currently the most effective standard-of-care chemotherapy based on its ability to prolong survival of patients with newly diagnosed MGMT-methylated GBM. Blood-brain barrier (BBB) permeable agents effective against TMZ-resistant GBMs (i.e. recurrent GBM, MGMT unmethylated GBM) are desperately needed. Lantern Pharma is advancing LP-184, an acylfulvene prodrug activated by the enzyme PTGR1, in GBM. In an MGMT expressing TMZ resistant GBM PDX model, LP-184 was found to be ~5000X more potent than TMZ. DNA damage induced by acylfulvenes is primarily repaired via transcription-coupled nucleotide excision repair (TC-NER) mediated by ERCC complexes and gene set variation analyses associate LP-184 cell sensitivity with low TC-NER. ERCC3 is a key NER factor that is proteolytically degraded in response to the FDA approved BBB permeable diuretic, spironolactone (SP). After verifying that spironolactone induces rapid ERCC3 degradation by up to 95% in GBM cells, we validated that SP-induced ERCC3 loss led to substantial increases in LP-184 response in vitro and in subcutaneous tumor xenografts. Co-treatment of GBM cells with LP-184 and 5 or 25 µM SP resulted in a 3-6 fold decrease in LP-184 IC50s in M1123, Mayo39 and U87 cultures in vitro. Mice bearing pre-established subcutaneous U87 xenografts were treated with SP alone, LP-184 alone or their combination. Tumors recurred after initial regression in 5/5 animals treated with LP-184 alone whereas tumors showed durable complete regression without recurrence in 4/5 animals treated with LP-184 + SP. LP-184 is a promising chemotherapeutic with potential clinical translation in GBM patients. Our results indicate that LP-184 is MGMT-agnostic and effective in TMZ-resistant pre-clinical GBM models. Our findings also identify ERCC3-dependent TC-NER activity as a determinant of LP-184 synthetic lethality predicting that LP-184’s therapeutic potential will be significantly enhanced in patients with intrinsic or spironolactone-induced NER deficient tumors.
NIMG-75. REPEATABILITY OF MANUAL SEGMENTATION OF GLIOBLASTOMA ON MRI - QUALITY ASSURANCE FOR A QUANTITATIVE MRI RADIOMICS REPEATABILITY STUDY
Authors: Edward Chan, Philip Martin, Caterina Brighi, Sugendran Pillay, Lois Holloway, Peter Metcalfe, Eng-Siew Koh
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Accurate and repeatable imaging segmentation of glioblastomas is important for effective radiomics modelling of clinical endpoints such as survival and treatment response. Manual and even automated segmentation are prone to variability. The primary objective of this study is to evaluate the repeatability of manually segmented glioblastomas on MRI which will serve as quality assurance for a quantitative MRI radiomics repeatability study. METHODS MRI datasets from n=19 patients with recurrent glioblastoma extracted from The Cancer Imaging Archive (RIDER Neuro MRI dataset) comprised of test-retest scans (time-point 1 and 2) acquired on average 2 days apart. The MRI protocol consisted of dynamic contrast-enhanced 3D FLASH using 0.1mmol/kg Magnevist intravenous injection at 3cc/second (TR 3.8ms, TE 1.8ms, 5mm slices, flip angle 25°), contrast-enhanced 3D FLASH (TR 8.6ms, TE 4.1ms, 1mm slices, flip angle 20°) and contrast-enhanced 3D FLAIR (TR 6000ms, TE 353ms, TI 2200ms, 1mm slices, flip angle 180°) on a 1.5T magnet. Contrast enhancing tumour from n=38 MRI scans were manually segmented by a radiologist slice by slice using contrast-enhanced 3D FLASH T1-weighted images on MIM software (v6.9.5). All cases at time-point 1 were contoured before contouring commenced for time-point 2 in the same order. Repeatability and spatial overlap was assessed by Dice similarity coefficient (DSC), Hausdorff distance (HD) and centroid shift. RESULTS A comparison of time-point 1 and 2 demonstrated the median DSC for n=19 cases was 0.84 (interquartile range 0.07), mean HD was only 0.1cm and mean centroid shift was 0.2cm. CONCLUSION High repeatability and spatial overlap of manually segmented contrast enhancing regions of recurrent glioblastoma were achieved on serial MRI. This substantiates a high level of repeatability which forms a core component of an MRI radiomics platform under development.